Today a certain number of pharmaceutical products exist to treat local infections or diseases, such as:                suckable tablets for the treatments of mouth ulcers, stomatitis, gingivitis, glossitis, etc. . . .        gels and creams for oral, vaginal, and rectal (hemorrhoids), and ocular treatments. As examples:                    Willmott's application WO 01/70271 protects a mixture of carrageenan and Sclerotium gum for skin applications surfactant free, the name of this application being: “ACID STABLE BASE COMPOSITIONS FOR PREPARING SURFACTANT FREE TOPICAL COMPOSITIONS”. Indeed sometime the surfactant irritate the mucous membranes specifically when these are destroyed.            the PCT application WO0056366 protects “A pharmaceutical composition adapted for use as a spermicide, the composition comprising a gel-microemulsion comprising an oil-in-water microemulsion and a polymeric hydrogel. The gel microemulsion can be used in a spermicidal method. Also, a gel microemulsion pharmaceutical composition adapted for use as a formulation base for additional therapeutic agents.”            The most important ingredients in the gel are Cremophor® ELO and Phospholipids (Phospholipon®). These two ingredients form a microemulsion incorporated in a lambda carrageenan polymeric gel for a vaginal applications.                        liquids for the nasal route (nasal solutes) and for the ocular route (eye lotions). As examples:                    OGAWA protects through his U.S. Pat. No. 4,910,25 a solution containing benzoylphenylacetic acid and its salts for treating inflammatory disease by topical application. The other ingredients used are just pH adjusters (buffer solutions) to maintain a pH around 6 avoiding eyes irritation.            The PCT/AU91/0063 protects eye drops containing phospholips and or hyaluronic acid dispersed in a carrier (propylene glycol).            A physiological salt is added in the purpose to maintain a good isotonicity of the medium.                        
Unfortunately these products have very short action duration, mechanically or therapeutically speaking, from a therapeutic standpoint because of a perpetual “washing out” of these mucous membranes by the secretions.
Indeed nothing in Willmott's application, no more in Ogawa's application, in the PCT application WO0056366 and in the PCT/AU91/0063, speaks about a prolonged release at the targetted point.
So, repeated local administrations are necessary and in certain cases, are not very pleasant for the patient.
Therefore it appears necessary, for the comfort of the patient, to have systems that make it possible to maintain local action duration more substantial than simple creams, in order to reduce the number of applications per day.
Broadly speaking, any system that makes it possible to prolong the mechanical action (lubricating action for example) or the therapeutic effect of an active ingredient in the organism, is called “prolonged effect or programmed release form”.
Today most of the systems having a programmed release, have been developed under solid form.
For the oral route, different kinds of tablets have been developed, called matrix (inert, plastic and oily matrices), which slowly release the active ingredient in the stomach or in the intestine.
In a purpose to obtain a potential better bioavailability, different sustained release microgranules contained in a hard capsule were developed, too. After the opening of the hard capsule, each microgranule slowly releases the active ingredient all along the intestinal tract, like if it was a small matrix.
Among all the patents filed in this field, we can cite inter alia,                The international application WO 03101424 mentioning iota carrageenans and other gum like hydroxypropylmethylcellulose or xanthan for the realization of matrices having prolonged release under solid form. In this application the applicant gives the name of “swelling modified system” or “gelling matrix modified release system” to his matrix. This qualification is due to the fact the gums are going to swell in aqueous medium, and slowly releasing the active contained in the mixture of gums. Sodium docecyl sulfate is added in purpose to increase the solubility of the active.        The U.S. Pat. No. 6,355,272, protecting a mixture of lambda carrageenan and actives in the purpose to form granules. These granules can to be compressed (tablets) or filled in hard capsules (granules) or to form pellets (small beads). Therefore these different forms are gradually going to release over the time in the digestive tract, the active ingredients. Some others ingredients can be added like hydroxypropylmethylcellulose or hydroxypropyl cellulose.        The international application WO 0100177 concerning a combination of amoxycycline, a gum (cellulose, cellulose esters or ethers, xanthan gum and carrageenan) associated or not with phospholipids. The mixture is transformed under the form of tablets, capsules or granules for a prolonged release of the antibiotic.        And the Hercules' U.S. Pat. No. 6,358,525 protecting different hydroxypropylcellulose and hydrocolloid based compositions containing another polysaccharide selected from the group of guar, agar, algin, gellan, carrageenan, etc. . . . . These compositions are under the form of tablets in order to slow down the availability of the active substances to the organism.        
In the same concept as for the oral route, sustained release systems have been developed for the intramuscular route: implants. These are small tablets placed under the skin slowly releasing the active due to the washing out of the physiological liquids (blood, lymph). Most of the actives are hormones.
Likewise skin can be a route for a slow release of an active. The programmed systems developed are patches or transdermal systems. A patch is a solid form more or less pasty, releasing the active like from a matrix, but this releasing depends of the solvent contained in the transdermal system which is going to increase the permeability of the skin. By this fact the active solubilized in this solvent goes through the skin and arrives in the blood circulation. Lot of applications have been developed: nicotine patches, scopolamine patches, isosorbide patches, etc . . . .
However these different forms, matrices, microgranules implants and transdermal systems have been conceived for a systemic action and not for a local treatment.
Contrary to the previous innovations, some solid forms slowly releasing actives for a local action, have been developed for the ocular and vaginal route.
In the case of the ocular route some forms are called Inserts. Different forms are actually commercialized like:                pre-cast hydrophilic matrices or hydrophilic lenses, which are considered as reservoirs because they are capable of being hydrated to nearly 85%. However the re-release of active ingredient contained in this reservoir is quite rapid.        erodable soluble implants impregnated with active ingredients (oval plates or pellets). Placed in the conjunctival cul-de-sac, they saturate quickly with lachrymal liquid. The liberation of the active ingredient is done by progressive dissolution of the support. A concrete example of this system is the hydroxypropylcellulose-based product Lacrisert®.        
For the vaginal route most of the solid forms are tablets.
As previously, the tablets can very well offer a prolonged release in situ under the washing out of the vaginal secretions.
However the administration of such forms is not practical for the patient and a rejection may occur after a certain time, if the form itself does not show adhesive properties.
As an example, the PCT application WO2007035954 protects sustained release misoprostol tablets for the vaginal route where the cellulosic excipient possesses adhesive properties. By this fact the active ingredient is slowly release and can locally or systemically acts.
If solid forms permit to control more or less the release of an active all along the time, unfortunately their action is more systemic than local action.
The best form for a local action would be a liquid or pasty form. But here too, some difficulties appear.
Indeed to prolong the action of a liquid or pasty form at the local application site, is very difficult due to the fact that secretions of the mucous membranes are going to dilute the product under a perpetual washing out of these, like saliva, tears, nasal secretions, vaginal secretions, etc . . . .
Despite this difficulty some developments have been done in the field.
The first developments to increase the release time of a liquid or pasty form at the local application site are based on a physical transformation of the liquid form.
This physical transformation is called “in situ gel formation”.
We understand by “in situ gel formation”, a physical transformation of the cream or liquid under the physiological parameters like temperature of the body or the electrolytes and proteins present in the physiologic liquids, or pH of the secretions themselves. The physical transformation is an increasing of the cream or liquid viscosity. The viscosity increasing onto the targeted organ or membrane, permits, of cause, a slow release of the active under the washing out at the local application site.
Based on the in situ gel formation by complexation, reaction between formulation and ions or proteins of the secretion, lot of patents have been filed. Most of them are for the ocular route like soluble gels.
These slow down the release of the active ingredient because of their elevated viscosity. The viscosity prolongs the contact time of the active ingredient onto the cornea and in the conjunctival cul-de-sac. This intensification of the action is due to the slowing down of the elimination process in the lachrymal channel, due to the viscosity of the product.
These gels are generally developed with water-soluble polymeric molecules such as polyvinyl alcohol, cellulose derivatives, and acrylic derivatives.
As examples we can cite works done by:                Wang and Hammarlung (1) on gels of polyvinyl alcohol and of hydroxypropylmethyl cellulose containing homatropine hypobromite having a myotic effect.        Haas and Coll. (2) on methylcellulose gels containing pilocarpine.        Goldberg and Coll. (3) as well as those of Mandell and Coll. (4) and March and Coll. (5) on high viscosity acrylic gels containing pilocarpine hydrochlorate.        Schoenwald and Coll. (6) on Carbopol® gels containing prednisolone acetate        
Other polymers can be used with the aim of delaying the release of the active ingredient such as alginic acid (Carteol® LP), and gellan gums (Timoptol®).
As examples:                the Japanese patent JP 2001501194 describes a liquid which is formed an in situ gel when it is applied, under eye drops, to the cornea. The Gelrite® component, a deactylated gellan gum forms an in situ gel by combination with the cations of the tears        The U.S. Pat. No. 5,403,841 and EP 0424043, carrageenan gels seeing their viscosity increasing in contact with sodium ions or proteins contained in the tears.        The U.S. Pat. No. 5,965,152, describes anionic interactions between the miotic or mydriatic agent and a viscoelastic polymer like an anionic viscoelastic polymer and a cationic miotic or mydriatic agent. Placed in the eye, the cationic agent of the composition, may be released by displacement of endogenous sodium or potassium ions present in the tears. As an example the anionic viscoelastic polymer acid may be sodium hyaluronate or chondroitin sulfate, and the cationic agent may be the mydriatic agent atropine sulfate or the miotic agent pilocarpine. In this case the composition reacts like an exchange ion resin between the sodium of the tears and the active ingredient fixed on the viscoelastic polymer.        
Likewise, based on the in situ gel formation by temperature elevation, different patents have been filed like:                U.S. Pat. No. 5,618,800 (Kabra et al.) protecting cellulose ether gels: viscosity increases under the temperature of the eyes.        U.S. Pat. No. 4,188,373, protects the polyoxyethylene-polyoxypropylene copolymer having a transition sol-gel temperature between 25° C. and 35° C. This means that under 25° C. the composition is liquid. Above 35° C. an in situ gel is formed        
The last in situ gel formation mechanism is based on pH sensitivity. As it is described in U.S. Pat. No. 4,136,173 the xanthan gum/locust bean mixture shows a liquid aspect at a pH between 3.5 and 5. Above 5, this mixture becomes solid.
The U.S. Pat. No. 4,474,751 combines all the in situ gel formation mechanisms described previously. Indeed the ingredient selected, the tetra ethylene diamine block copolymer of polyoxyethylene-polyoxypropylene reacts under temperature, pH and ions and becomes more or less liquid or viscous
The second way to obtain a slow release at the local application site is achieved with bio-adhesive compositions.
By “bio-adhesive” we understand the capacity of a biological or synthetic material to “stick” onto a biological or mucous membrane.
The sticky effect of the bio adhesive composition comes from the fact the material is able to form chemical bonds with the substrate, the mucous membrane.
The most important bonds formed with the bio adhesive material, are Hydrogen bonds. It is a reaction which occurs between the OH groups of the bio adhesive material and the water of the secretion covering the mucous membrane.
Most of the studies realized in this field concern solid forms.
Indeed under the solid form the bio material shows stronger reaction with the substrate because the OH groups are totally available for forming hydrogen bonds. Under a liquid form the OH groups of the bio material are already combined with water decreasing by this fact, the potential to form hydrogen bonds with the substrate.
Under solid forms, for the ocular route some studies have been done using Carbopol® as bio adhesive material (HO-WAH HUI and Coll. [7]). But the bio-adhesion mechanism could not be perfectly established.
In the same way, some studies have been done for the nasal and vaginal route using, Carbopol® or derivatives of polyacrylic acid polymers, too.
As examples:                the U.S. Pat. No. 4,226,848 mentions the use of cellulosic derivatives and acrylic polymers as bio materials for the nasal route. The final product can be tablets, granules, powders.        The Japanese patent 130421/78 protects a polyacrylic acid polymer/hydroxypropylcellulose bio-adhesive mixture under a solid form for the vaginal route to treat a carcinoma.        
These solid forms swell when they are in contact of the body fluid.
Compared with the latest, studies for the oral route, specifically the mouth, are more important.
The forms known as bio-adhesives for the oral route are mostly tablets or patches. The ingredients known as bio-adhesives tested within this application framework are:                Carbopol® (polyacrylates derivatives)        carboxyvinyl polymers and derivatives        hydroxypropylmethylcellulose and derivatives        Natural proteins from milk        gelatin        chitosan        and gum of acacia.        
As examples the following patents can be cited:                MY125919 where the bio adhesive material is a mixture of cellulose, starch, lactose, water soluble polymer and a cross linked polycarboxilic polymer.        U.S. Pat. No. 6,977,083 where le bio adhesive material is a mixture of polyacrylates and sodium carboxymethylcellulose for a testosterone bio adhesive tablet.        WO 704342 where the bio adhesivity is obtained through a mixture of partly hydrolyzed PVP alcohol, polyethylene oxide, polyacrylates and hydroxypropylmethylcellulose.        Etc. . . .        
However even if the tablets and the patches ensure a prolonged release of the active ingredient in any cavities, the maintenance during 8 hours of such forms in the mouth or in the vagina, is not conceivable for a patient.
Therefore liquids or pasty bio adhesive forms would seem better tolerated.
Under bio adhesive liquids or creams for vaginal, rectal and nasal routes, some patents have already been filed using approximately the same ingredients as those for the solid forms.
As example:                US Patent Publ. 2015/147282, US Patent Publ. 2014/186279 and EP0975331 protect a mixture containing a neutral diacyl lipid, a phospholipid, tocopherol and a biocompatible solvent. This mixture in contact the body fluid, like vaginal secretion, becomes bio adhesive by formation of lamellar structure where crystals are dispersed. The mechanism seems similar to an in situ gel formation, emphasized by addition of biomaterial. The prolonged release from these compositions can be counted by hours or by days.        HK1088829 and WO2004073597 protect a mixture containing particles of alginate dispersed in a non aqueous diluent, like glycerol or propylene glycol. In contact with body fluid, the particles swell, coalesce and stick onto the surface which can be the vaginal mucous membrane.        WO2005115339 has registered a liquid mixture containing a mucoadhesive ingredient, polyacrylic acid polymer, a permeation enhancer, phospholipids and a solvent having bio adhesive properties and which can be applied on nasal and vaginal membrane. The Applicant mentions that this mixture is polysaccharides free.        U.S. Pat. No. 6,465,626 and US Patent Publ. 2001/053359 protect compositions for nasal applications where the components are chitosan (bio adhesive material), gellan (in situ gel formation), and an alginate solution as suspending material for the gellan microsphere. Under the moisture of the nasal mucous, the particles swell and stick to the membrane.        U.S. Pat. No. 6,060,077 protects a vaginal bio adhesive liquid containing oestrogen as active, a Lipophile solvent (triglycerides), an hydrophilic gel forming agent chosen from carboxyvinylic acids, cellulose derivatives, gelatin, xanthan gum and guar gum, a gelling agent for the lipophilic phase (silica) and a hydro dispersible agent like polyoxyethylen glycol. This bio adhesive liquid composition is containing in a soft capsule. After its opening the liquid forms an emulsion onto the vaginal mucosa from which the active is slowly released. As the gelling agent shows bioadhesive properties, no flow is observed due to the gel fixation onto the mucosa. These properties can be increased by using buffer solutions. Indeed the Applicant considers that electrostatic bonds can be formed between the positive charges of the product and the negative ones of the mucous emphasized by the buffer solutions        US Patent Publication 2003/180366 protects liposome compositions where the most important ingredient is phospholipid. These phospholipids are associated with hydrophobic material like oils in the purpose to form the barrier of the liposomes. To stabilize this barrier some polymers are added: cellulose derivatives or polyethylene, polypropylene polyurethane polyamide derivatives. Here too, this bio-adhesive composition is administrated to the vaginal cavity under soft capsule form. One of absorption mechanism described in this application is based on the Vander Waal bonds formed between the liposomes and the vaginal mucosa. This bending potentially conducts to a sustained release.        KR100292027 protects a bio-adhesive composition for the rectal route. The adhesive components are carbopol and polycarbophil associated with poloxamers and some other ingredients. The poloxamers have the property under temperature to become liquid. In this case the bio-adhesive properties of carbopol and the in situ gel formation mechanism are combined together.        WO9730693 protects compositions similar to the previous one. Instead of using carbopol or polycarbophil as bio-adhesive ingredient, they protect chitosan and alginate. It seems that the NH2 groups of these excipients are going to react with the OH group of the poloxamer, permitting to adjust the in situ gelling temperature of the mixture. On the another hand, the OH group of alginate and chitosan react, too, to the oligosaccharides of the mucous increasing the bioadhesivity of the formulation.        U.S. Pat. No. 6,159,491 protects the use of a mixture of Carbopol® (Polycarbophil®), carrageenans and agarose highly purified in the purpose to have a release in two steps. In the present case the carrageenans are used as gelling agent, delaying the release of the active substances and Carbopol® as bio-adhesive.        U.S. Pat. Nos. 5,069,906 and 4,983,393 mention carrageenan as a matrix agent only, in the purpose to delay the release of the actives. The bio-adhesive character is not mentioned.        
For the oral route, most of the developments have been done for the gastro intestinal tract.
Indeed we cite as examples:                U.S. Pat. No. 6,610,667 protects a composition of which the principal agent of bio-adhesion is alginate and at a lesser degree, other hydrocolloids such as the xanthan gum, galactomananes, glucomananes and carrageenans. The application is mainly centered around the combination alginate/gum xanthane or alginate/galactomananes or glucomananes. Furthermore, the esophagus is far from being a cavity easy to reach by hand.        GB 2324725 proposes compositions containing alginates and bicarbonate in purpose to cover the esophageal mucous (GB 2324725). The bio-adhesive material is alginates having a special grade defined by the mannuronic/guluronic ratio. This ratio permits to have a low viscous allowing the alginate gel to stick onto the gastro intestinal mucosa. The Applicant mentions that the alginates react with the mucin of saliva and gastro intestinal fluid, but does not explain how.        US Publ. 2003/198619 and WO03053400, protect a combination of polysaccharides (pentosan polysulfate), an enhancer (EDTA, Bile salt), a non ionic surfactant like Cremophor® and a viscosity reducing agent like polyethylene 5 castor oil. This bio adhesive liquid is contained in a soft capsule. After its opening in the gastric fluid, the bio adhesive liquid covers the stomach mucous membrane in purpose to increase the time release of the active. But more than a real bioadhesivity mechanism which can occur, it is an in situ gel mechanism which takes place.        The U.S. Pat. Nos. 5,672,356 and 6,242,004 mention the use of carrageenans as gelling agent delaying the release of the active ingredient, the bio-adhesion being supplied by the copolymer of methylvinyl ether and maleic anhydride.        
Specifically applied on the mouth mucous, the patent publication US Patent Publ. 2007/189983 protects a tooth whitening composition having bio adhesive properties where the biomaterial are xanthan gum, carbomers and PVP copolymer. To maintain the active for a long time on the teeth a film forming agent is added, ethylcellulose. No mechanism of adhesion is described in the patent.
In an opposite way, the PCT application WO2007073346, protects a bio adhesive composition with a quick dissolution time in the mouth. The biomaterial is alginates. No mechanism of adhesion is described in this application.
Even if the bio adhesive liquid or pasty forms previously described, seem better tolerated by the patient, the washing out of the mucous membranes by the secretion conducts to a progressive dilution of the hydrogen bonds of the bio adhesive creamy product, decreasing by this fact, the time release at the targeted point.
Indeed under the water contained in the secretion, the strength of the hydrogen bonds towards the substrate decreases and slowly release the product from its targeted site. The product progressively loses its bio adhesive properties. This phenomenon is less important when the bio-adhesive pasty forms combined hydrogen bonds with the substrate and the in situ gel formation mechanisms.
To overcome this problem, a stronger binding between the substrate and the liquid product must be needed.
One way is possible, the creation of stronger bonds (chemical or physical) with the substrate other than hydrogen bonds.
The US patent Publ. 2001/053359 describes different kinds of bonds other than hydrogen bonds, which can occur with the substrate: Van der Waals bonds, ionic bonds and polymer entanglement. The last is more a physical binding than a chemical binding.
Some patents touch on some potential combinations between the chemical groups of the bio adhesive material and the substrate, other than hydrogen bonds, like those previously cited:                WO9730693: interaction between NH2 groups of the bioadhesive excipients and OH group of the poloxamer and between OH group of alginate and chitosan and oligosaccharides of the mucous        U.S. Pat. No. 6,060,077: electrostatic bonds formed between the positive charges of the product and the negative ones of the mucous.        US Patent Publ. 2003/180366: Van der Waal bonds formed between the liposomes and the vaginal mucosa.        
U.S. Pat. No. 6,391,294 describes different kinds of biomaterials, anionic and cationic, which are able to react together to form a bio-adhesive film on the body surface where the mixtures are applied. Among them carrageenan are cited. But U.S. Pat. No. 6,391,294 protects two liquids, one containing an anionic polymer, the other one, the cationic polymers. These two solutions must be applied simultaneously or a little differently in purpose to form the film by ionic interaction between the two polymers.
The carrageenan effectively possess a reactive group on its structure, a sulfate group (SO42−), which is able to react with positive charged molecules like those containing an N+. This property has been used for blocking the growth of some micro organisms rich in N+ molecules.
This ability to form Van der Waals bonds between SO42− and positively charge molecules, has been already protected in two applications:                EP patent 125759 and the French patent FR 2542616 protect a gel to be applied on mouth and genital parties for curing candidosis. In these applications the carrageenan used is a denatured carrageenan in purpose to increase the number of sulfate groups which are going to react with the microorganism envelope rich in amines derivatives.        U.S. Pat. No. 5,658,893 protects a carrageenan liquid having the property to inhibit rotavirus infection. The sulfated polysaccharide interacts in the replication process of the virus due to the blockage of amine derivatives rich in N.        
Thus, after a thorough study of the literature in the field of the bio-adhesive forms having a prolonged release, it has been unable to find a bio-adhesive pasty form combining different kinds of bonds with the substrate, other than hydrogen bonds and in situ gel formation, in the purpose to reinforce the adhesion of the liquid product to the substrate, specifically the mucous membranes. The aim of this reinforcement is to obtain a form having a prolonged release of long duration, greater than 2 hours.
Given this situation and to remedy it, the invention offers an original concept of viscous liquid compositions intended for the realization of pasty or liquid forms having prolonged action and/or release for local applications onto cavities easily reached by hand. These compositions are characterized in that long lasting and/or prolonged action and/or release of the active ingredient is obtained, not only by hydrogen bonds, but by chemical and physical reactions between the biomaterial and the components of the substrate, too. A film is formed at the surface of the mucous membrane, having reinforced bio-adhesive capacity. Under the effect of a permanent washing of the mucous membranes by the secretions, the action and/or release of the product or of the active entrapped in the aforementioned film, is greater than 2 hours and can be modulate by additives.